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Details for Patent: ➤ Try a Free Trial

Title:

Controlled-release compositions

Abstract:

A solid dosage formulation having a core with a pharmacological agent dispersed in a first controlled-release matrix from which release of the agent is relatively slow; and a coat formed over the core and having the agent dispersed in a second controlled-release matrix from which release of the agent is relatively fast. The first matrix can be a cross-linked high amylose starch and the second matrix can be a mixture of polyvinyl acetate and polyvinylpyrrolidone.

1. A solid dosage formulation comprising: a core comprising tramadol dispersed in a first controlled-release matrix comprising cross-linked high amylose starch; and a compression coat formed over the core and comprising tramadol dispersed in a second controlled-release matrix comprising a mixture of polyvinyl acetate and polyvinylpyrrolidone at a weight ratio of about 8:2 such that the mixture comprises from about 30% to about 65% by weight of the coat, wherein the initial rate of release of tramadol from the second controlled-release matrix is at least twice the initial rate of release of tramadol from the first controlled release matrix when measured separately for each matrix material in a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm.

2. The formulation of claim 1, wherein the tramadol is present in the formulation as an ionic salt.

3. The formulation of claim 1, wherein the rate of release of tramadol from the second controlled-release matrix is between three and nine times the rate of release of tramadol from the first controlled-release matrix.

4. The formulation of claim 1, wherein the rate of release of tramadol from the second controlled-release matrix is at least three times the rate of release of tramadol from the first controlled-release matrix.

5. The formulation of claim 1, wherein between 10% and 30% of tramadol present at 0 hours is released between 0 and 2 hours when tested in vitro using a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm.

6. The formulation of claim 1, wherein between 10% and 40% of the tramadol is released from the formulation between 0 and about 2 hours, between about 30% and 60% of the tramadol is released from the formulation between 2 and about 7 hours, between about 50% and 80% of the tramadol is released from the formulation between 7 and about 12 hours, and between about 80% and 100% of the tramadol is released from the formulation after about 20 hours.

7. The formulation of claim 1, wherein the ratio of the core to the coat (w/w) is between about 1 and about 0.1.

8. The formulation of claim 1, wherein the ratio of the tramadol in the core to the tramadol in the coat (w/w) is between about 0.6 and about 2.

9. The formulation of claim 1, wherein the coat is between about 5% and about 90% by weight tramadol.

10. The formulation of claim 1, wherein the ratio of the matrix of the coat to the tramadol of the coat (w/w) is between about 0.7 and about 4.

11. The formulation of claim 1, wherein the ratio of the matrix of the core to the tramadol of the core (w/w) is between about 0.1 and about 10.

12. The formulation of claim 1, wherein the coat further comprises a binding agent.

13. The formulation of claim 12, wherein the binding agent is xanthan gum.

14. The formulation of claim 1, wherein the formulation is a tablet, and wherein the cross-linked high amylose starch comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising: (a) cross-linking high amylose starch, followed by (b) chemically modifying the cross-linked high amylose starch by hydroxypropylating the cross-linked high amylose starch, followed by (c) gelatinization, and (d) drying to obtain a powder of the controlled release excipient; wherein the cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80.degree. C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose in the cross-linked high amylose starch is at least 90% of that of the peak corresponding to amylose in the high amylose starch prior to (a).

15. The formulation of claim 1, wherein the core further comprises a lubricant.

16. The formulation of claim 1, wherein the coat further comprises a lubricant.

17. The formulation of claim 1, wherein the formulation is a tablet formulated for oral administration.

18. A controlled released tablet comprising: a compressed core comprising cross-linked high amylose starch and tramadol, or a salt thereof; and a coat formed over the core by compression, and comprising a mixture of polyvinyl acetate, polyvinylpyrrolidone, a binder, and tramadol; and wherein: the ratio of the core/coat (w/w) is between about 0.2 and 0.6; the ratio of the tramadol in the core to the tramadol in the coat is between about 0.7 and about 1; the ratio of polyvinyl acetate/polyvinylpyrrolidone (w/w) is about 8:2; and the rate of release of tramadol from the coat is at least twice the rate of release of tramadol from the core when measured by a USP Type I apparatus in 50 mM phosphate, pH 6.8, and between 50 and 150 rpm.

19. A method of administering a pharmacological agent, the method comprising administering to a patient a solid dosage formulation as defined in claim 1 or 18.

20. The formulation of claim 18, wherein the polyvinyl acetate has a molecular weight in the range from about 100,000 to about 1,000,000.

21. The formulation of claim 18, wherein the polyvinylpyrrolidone has a molecular weight in the range from about 10,000 to about 100,000.

22. The formulation of claim 18, wherein the formulation is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL within two hours of administration and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after administration.

23. The formulation of claim 22, wherein the maximum mean plasma concentration is less than 2.2 times the mean plasma concentration obtained 24 hours after administration.

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